Project Abstract This proposal outlines the scientific agenda for the COVID-19 Prevention Network (CoVPN) Vaccines Leadership Operations Center (LOC) for implementation of the first COVID-19 vaccine efficacy trial ?A Phase 3, Randomized, Stratified, Observer-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Immunogenicity of mRNA-1273 SARS-CoV-2 Vaccine in Adults Aged 18 Years and Older.? With the global COVID-19 pandemic, we recognize a significant need for vaccines that modify COVID-19 in SARS-CoV-2 infected individuals. Addressing this gap, the HVTN has joined 4 other National Institute of Health (NIH) clinical trial networks to form the CoVPN, an enhanced network dedicated to developing globally effective vaccines for SARS-CoV-2. Due to its extensive experience implementing HIV vaccine trials, the HIV Vaccine Trials Network (HVTN) LOC was selected to as the CoVPN vaccine LOC. This trial, a phase 3, placebo-controlled, double-blinded study will test the efficacy of mRNA-1273 SARS-CoV- 2, a lipid co-formulated messenger ribonucleic acid (mRNA) vaccine encoding the SARS-CoV-2 spike protein (S), to modify COVID-19 disease in adults 18 year of age and older. Participants will be recruited from clinical trial sites across the US, using data analytics to target high risk individuals with a diverse racial and ethnic profile. In addition, the CoVPN will use accessory community-based sites, staffed by clinical teams from the home sites and employ mobile clinics to enroll individuals in new high risk settings (e.g., meat packing plants). Participants will receive symptomatic screening for SARS-CoV-2 infection, and if they become infected will be monitored with frequent clinical check-ins and remote monitoring of vital signs. Infected individuals who progress to moderate-severe COVID-19 will be referred for hospitalization. All trial endpoint assays will be done at CoVPN laboratories, using validated assays for diagnosis and immune monitoring. Specific aims of this study are to demonstrate efficacy of mRNA-1273 SARS-CoV-2 to prevent COVID-19, to evaluate the safety and reactogenicity of 2 injections given 28 days apart, the assess the ability to prevent infection with SARS-CoV-2, the assess the ability to modify COVID-19 infection, to evaluate viral infection kinetics, and to evaluate the vaccine induced immune response. This initial efficacy trial will tell us much about the adaptive immune response in persons who receive a SARS-CoV-2 S protein based vaccine and about their ability to modify the disease course of COVID-19. In addition, it will improve our understanding of the dynamics and duration of these responses and will inform rational design and testing of preventive and therapeutic monoclonal antibody interventions. Lastly, the results of this trial will be used to assess registration of this vaccine product as well as to modify future COVID-19 vaccine trials planned over the next 12 months.